A mitochondrial protein called uncoupling protein 1 (UCP1) is thought to play an important role in the body's regulation of energy utilization. Such regulation provides widespread physiological controls, including body weight, appetite, glucose metabolism, temperature, immune responses, etc. Mechanistically, UCP1 is thought to create a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy consuming process (for review, see Nicholis & Locke (1984) Physiol. Rev. 64:1-64). Unfortunately, the role of UCP1 in physiologies, such as body weight regulation in large adult mammals, such as humans, cattle, pigs, etc., is likely to be limited, since there is little brown adipose tissue in such animals.
UCP2 is a second, related uncoupling protein that is much more widely expressed in large adult mammals (see, e.g. Fleury et al. (1997) Nat. Genet. 15:269-272 and Tartaglia et al. WO 96/05861). Consistent with a role in the regulation of energy utilization in general, and in diabetes and obesity in particular, the UCP2 gene is upregulated in response to fat feeding and maps to regions of the human and mouse genomes linked to hyperinsulinaemia and obesity.
More recently, a third structurally related UCP gene, UCP3 has been characterized and found to be preferentially expressed in skeletal muscle and brown adipose tissues; see Vidal-Puig et al. (1997) Biochem. Biophys. Res. Comm. 235:79-82 and Boss et al. (1997) FEBS Lett. 408:39-42. UCP3 has been linked to a number of disorders associated with the control of energy expenditure, including obesity and diabetes.
The identification of compounds that modulate the activity and/or expression of UCP3 represents an attractive approach to the development of therapeutic agents for the treatment of conditions and disorders associated with energy utilization.